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The New England 

Journal of Medicine 

©Copyright, 1990, by the Massachusetts Medical Society 

Volume 323 

JULY 5, 1990 

Number 1 


Daniel Rudman, M.D., Axel G. Feller, M.D., Hoskote S. Nagraj, M.D., Gregory A. Gergans, M.D. 

Pardee Y. Lalitha, M.D., Allen F. Goldberg, D.D.S., Robert A. Schlenker, Ph.D., 

Lester Cohn, M.D., Inge W. Rudman, B.S., and Dale E. Mattson, Ph.D. 

Abstract Background. The declining activity of the 
growth hormone-insulin-like growth factor I (IGF-I) axis 
with advancing age may contribute to the decrease in lean 
body mass and the increase in mass of adipose tissue that 
occur with aging. 

Methods. To test this hypothesis, we studied 21 
healthy men from 61 to 81 years old who had plasma 
IGF-I concentrations of less than 350 U per liter during 
a six-month base-line period and a six-month treatment 
period that followed. During the treatment period, 12 men 
(group 1) received approximately 0.03 mg of biosynthetic 
human growth hormone per kilogram of body weight sub- 
cutaneously three times a week, and 9 men (group 2) re- 
ceived no treatment. Plasma IGF-I levels were measured 
monthly. At the end of each period we measured lean 
body mass, the mass of adipose tissue, skin thickness 
(epidermis plus dermis), and bone density at nine skeletal 

Results. In group 1 , the mean plasma IGF-I level rose 
into the youthful range of 500 to 1500 U per liter during 
treatment, whereas in group 2 it remained below 350 U per 
liter. The administration of human growth hormone for six 
months in group 1 was accompanied by an 8.8 percent 
increase in lean body mass, a 14.4 percent decrease in 
adipose-tissue mass, and a 1.6 percent increase in aver- 
age lumbar vertebral bone density (P<0.05 in each in- 
stance). Skin thickness increased 7.1 percent (P = 0.07). 
There was no significant change in the bone density of the 
radius or proximal femur. In group 2 there was no signifi- 
cant change in lean body mass, the mass of adipose tis- 
sue, skin thickness, or bone density during treatment. 

Conclusions. Diminished secretion of growth hor- 
mone is responsible in part for the decrease of lean body 
mass, the expansion of adipose-tissue mass, and the thin- 
ning of the skin that occur in old age. (N Engl J Med 1990; 

IN middle and late adulthood all people experience 
a series of progressive alterations in body composi- 
tion. 1 The lean body mass shrinks and the mass of 
adipose tissue expands. The contraction in lean body 
mass reflects atrophic processes in skeletal muscle, liv- 
er, kidney, spleen, skin, and bone. 

These structural changes have been considered un- 
avoidable results of aging. 1 It has recently been pro- 
posed, however, that reduced availability of growth hor- 
mone in late adulthood may contribute to such 
changes. 1 ' 2 This proposal is based on two lines of evi- 
dence. First, after about the age of 30, the secretion of 
growth hormone by the pituitary gland tends to de- 
cline. 1 ' 3 ' 4 Since growth hormone is secreted in pulses, 
mostly during the early hours of sleep, it is difficult to 

From the Department of Medicine, Medical College of Wisconsin, Milwaukee 
(D.R., I.W.R.); the Medical Service, Veterans Affairs Medical Center, Milwaukee 
(D.R.); the Department of Medicine, Chicago Medical School, North Chicago 
(A.G.F., H.S.N., GA.G., P.Y.L., L.C.); the Medicine (A.G.F., H.S.N., P.Y.L.), Nu- 
clear Medicine (GA.G), and Dental (A.F.G) Services, Veterans Affairs Medical 
Center, North Chicago; the Argonne National Laboratory, Argonne, 111. (R.A.S.); 
and the Epidemiology-Biometry Program, University of Illinois School of Public 
Health, Chicago (D.E.M.). 

Supported by grants from the Department of Veterans Affairs and Eli Lilly and 
Co., and by a grant (1D31 PE95008-02) from the Public Health Service. 

measure the 24-hour secretion of the substance direct- 
ly. Growth hormone secretion can be measured indi- 
rectly, however, by measuring the plasma concentration 
of insulin-like growth factor I (IGF-I, also known as so- 
matomedin C), which is produced and released by the 
liver and perhaps other tissues in response to growth 
hormone. 1 There is little diurnal variation in the plas- 
ma IGF-I concentration, and measurements of it are 
therefore a convenient indicator of growth hormone se- 
cretion. 1 Plasma IGF-I concentrations decline with ad- 
vancing age in healthy adults. 1 ' 4 ' 6 Less than 5 percent 
of the healthy men 20 to 40 years old have plasma 
IGF-I values of less than 350 U per liter, but the values 
are below this figure in 30 percent of the healthy men 
over 60. 4 Likewise, the nocturnal pulses of growth hor- 
mone secretion become smaller or disappear with ad- 
vanced age. If the plasma concentration of IGF-I falls 
below 350 U per liter in older adults, no spontaneous 
circulating pulses of growth hormone can be detected 
by currently available radioimmunoassay methods. 4 
The concomitant decline in plasma concentrations of 
both hormones supports the view that the decrease in 
IGF-I results from diminished growth hormone secre- 
tion. 4 ' 6 Second, diminished secretion of growth hor- 

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July 5, 1990 

mone is accompanied not only by a fall in the plasma 
IGF-I concentration, but also by atrophy of the lean 
body mass and expansion of the mass of adipose tis- 
sue. 1 These alterations in body composition caused by 
growth hormone deficiency can be reversed by re- 
placement doses of the hormone, as experiments in 
rodents,' children, 8 ' 9 and adults 20 to 50 years old 10 " 13 
have shown. These findings suggest that the atrophy 
of the lean body mass and its component organs and 
the enlargement of the mass of adipose tissue that are 
characteristic of the elderly result at least in part from 
diminished secretion of growth hormone. 1 ' 2 If so, the 
age-related changes in body composition should be 
correctable in part by the administration of human 
growth hormone, now readily available as a biosyn- 
thetic product. 14 

In this study we administered biosynthetic human 
growth hormone for six months to 12 healthy men from 
61 to 81 years old whose plasma IGF-I concentrations 
were below 350 U per liter, and we measured the ef- 
fects on plasma IGF-I concentration, lean body mass, 
adipose-tissue mass, skin (dermal plus epidermal) 
thickness, regional bone density, and mandibular- 
height ratio (the height of the alveolar ridge divided by 
the total height of the mandible). The measurement of 
the mandible was included to test the hypothesis that 
the age-related involution of dental bone results in part 
from the loss of stimulation by growth hormone. 1 In ad- 
dition, the men were monitored for possible adverse ef- 
fects of the hormone by means of interviews, physical 
examinations, and standard laboratory tests. Nine men 
matched for age and with similar plasma IGF-I concen- 
trations served as controls. 


Healthy men who were 61 or older and living in the community 
were recruited through newspaper advertisements followed by an in- 
terview. Entry criteria (available from the authors on request) includ- 
ed body weight of 90 to 120 percent of the standard for age, the abil- 
ity to administer growth hormone to oneself subcutaneously, and the 
absence of indications of major disease. Ninety-five men who an- 
swered the advertisements met criteria that could be ascertained by 
interview. Their plasma IGF-I concentrations were then determined 
twice at an interval of four weeks. Consistent with the results of a 
previous study, 13 the plasma IGF-I values in these men ranged from 
100 to 2400 U per liter, with an average of 500 U per liter. Thirty- 
three of the men had plasma IGF-I values of less than 350 U per liter 
on both occasions. These 33 men were then further evaluated by a 
medical-history taking, physical examination, differential blood 
count, urinalysis, blood-chemistry tests, chest radiography, and elec- 
trocardiography. Twenty-six subjects (1 black and 25 white) met all 
the entry criteria and were enrolled in the 12-month protocol sum- 
marized in Table 1. 

Study Periods 

The men were seen at regular intervals and tested as shown in Ta- 
ble 1 during the first week of the first, third, and sixth months of the 
base-line period. Five men dropped out of the study during these six 
months (four for personal reasons and one because carcinoma of the 
prostate was detected). 

At the beginning of the seventh month, the 2 1 men who had 
completed the base-line period were randomly assigned to group 1 
(growth hormone group) or group 2 (control group) in a ratio of 3 to 
2. The randomization table was generated by a computer program 

Table 1 . Schedule of Tests during the Base-Line 
and Treatment Periods. 




Treatment Period 










8 9 10 11 



Physical examination 





X X X X 







X X X X 







X X X X 


Blood chemistry* 





X X X X 


Chest radiography 












Total body potassiumf 



Skin thickness^: 



Bone density* § 



Mandibular-height ratio*H 



Plasma IGF-I 





X X X X 


Biosynthetic growth 


X X X X 


*Tests included a complete blood count, hematocrit, blood indexes, and the measurement af- 
ter an overnight fast of plasma glucose, urea nitrogen, creatinine, uric acid, sodium, potassium, 
chloride, carbon dioxide, phosphate, calcium, total protein, albumin, alkaline phosphatase, as- 
partate aminotransferase, lactic dehydrogenase, bilirubin, cholesterol, triglyceride high-density 
lipoprotein cholesterol, and glycosylated hemoglobin levels. Tests were performed at the 
North Chicago Veterans Affairs Medical Center laboratories. 

"("Total body potassium levels (lean body mass and adipose-tissue mass) were measured 
according to the method of Flynn et al. 1 ' 1 

^Calculated as the sum of the skin thicknesses of the right and left dorsal hand and right and 
left volar forearm measured with a Harpcnden caliper according to the method of Lawrence and 

§Measured according to the method of Nagraj et al. 1 ' 

^Measured according to the method of Goldberg et al. Ii! 

||Measurcd at Nichols Laboratory, Los Angeles, according to the method of Furlanetto et al. IS 

** Administered to group 1 only. 

such that in each group of five men, three would be assigned to the 
growth hormone group and two to the control group. All 21 men (12 
in group 1 and 9 in group 2) completed the treatment period and 
constitute the study group for this report. Their clinical character- 
istics are summarized in Table 2. During the first week of the sev- 
enth month, the men in group 1 were instructed in the subcutane- 
ous administration of recombinant biosynthetic human growth 
hormone (2.6 IU per milligram of hormone; Eli Lilly). The initial 
dose was 0.03 mg per kilogram of body weight, injected three times 
a week at 8 a.m., the interval between injections being either one 
or two days. A sample of venous blood for plasma IGF-I assay was 
obtained each month 24 hours after a growth hormone injection. If 
the IGF-I level was below 500 U per liter, the dose of hormone was 
increased by 25 percent; if the IGF-I level was above 1500 U per li- 
ter, the dose was reduced by 25 percent. The men in group 2 re- 
ceived no injections. The schedule of tests for both groups during 
the treatment period is shown in Table 1. 

At the start of the base-line period, the project dietitian instructed 
each man to follow a diet that furnished 25 to 30 kcal per kilogram. 
The distribution of kilocalories among protein, carbohydrate, and fat 
was approximately 15 percent, 50 percent, and 35 percent, respec- 
tively. At each scheduled visit shown in Table 1, the dietitian analyzed 
each man's diet on the basis of a 24-hour dietary recall and instructed 
the subjects again about the standard diet. The men were told not 
to alter their lifestyles (including their use of tobacco or alcohol and 
their level of physical activity) during the 12-month study period. 

The study protocol was carried out with the informed consent of 
each subject and with the approval of the human-research commit- 
tees of the Medical College of Wisconsin, the Chicago Medical 
School, and the Veterans Affairs Medical Centers in North Chicago 
and Milwaukee. 

Statistical Analysis 

The methods used to measure each response variable and the lo- 
cations where the tests were performed are described in Table 1. 

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Vol. 323 No. 1 


Table 2. Clinical Characteristics of the Study Subjects. 


■ 1 

Group 2 


(N = I 


(N = 9) 

Median age (range) 

67 (61- 


68 (65-81) 

Percent of ideal body weight — 

103 (94- 


105 (99-117) 

median (range) 

Medical conditions (no. of subjects) 

Degenerative joint disease 



Benign prostatic hypertrophy 









Arteriosclerotic heart disease* 





Kidney stone 



Hiatus hernia 


Medications (no. of subjects) 

Nonsteroidal antiinflammatory drug 



Pilocarpine eyedrops 





*Defined as a history of myocardial infarction ( 
to coronary artery disease. 

ctrocardiograplnc abnormality ascribed 

The interassay coefficients of variation for the response variables 
were as follows: plasma IGF-I, 7.2 percent; lean body mass, 3.6 per- 
cent; adipose-tissue mass, 6.9 percent; skin thickness, 5.4 percent; 
and bone density, 2.3 percent (average of nine measured sites). 

P values based on two-tailed, matched-pair t-tests were calculat- 
ed for the comparisons between the 6-month and 12-month values 
in group 1 and group 2. In addition, for each response variable the 
6-month value was subtracted from the 12-month value to repre- 
sent the change in each subject. P values based on two-tailed, un- 
equal-variance, independent-sample t-tests were then calculated 
for the comparison of the changes in response variables between 
groups 1 and 2. 


Clinical Observations 

All the men remained healthy, and none had any 
changes in the results of differential blood count, uri- 
nalysis, blood-chemistry profile, chest radiography, 
electrocardiography, or echocardiography during the 
12-month protocol. Specifically, none had edema, fast- 
ing hyperglycemia (>6.6 mmol of glucose per liter), 
an increase in blood pressure to more than 160/90 
mm Hg, ventricular hypertrophy, or a local reaction to 
human growth hormone, nor did their serum cholester- 
ol or triglyceride concentrations change significantly. In 
group 1, however, both the mean (±SE) systolic blood 
pressure and fasting plasma glucose concentration 

were significantly higher (P<0.05 by matched-pair t- 
test) at the end of the experimental period than at the 
end of the base-line period (127.2±5.2 vs. 119.1 ±3.6 
mm Hg and 5.8±0.2 vs. 5.4±0.2 mmol per liter, re- 

Plasma IGF-I Concentration 

In group 1, the mean plasma IGF-I concentration 
ranged from 200 to 250 U per liter throughout the 
base-line period (Table 3). Within one month after the 
administration of growth hormone had been initiated, 
the mean IGF-I level rose to 830 U per liter (P<0.05), 
and it remained near this value for the next five 
months. Eight of the 12 men in group 1 required no 
adjustment in their initial dose of growth hormone. 
Two required an upward adjustment of 25 percent, 
and two required a downward adjustment of 25 per- 
cent. The mean plasma IGF-I concentration in group 
2 remained in the range of 180 to 300 U per liter 
throughout the base-line and treatment periods. 

Lean Body Mass, Adipose-Tissue Mass, Skin Thickness, 
Bone Density, and Mandibular-Height Ratio 

Table 4 shows the mean values for the other re- 
sponse variables at the end of the base-line period (6 
months) and the end of the treatment period (12 
months). There was no significant change in weight in 
either group. In group 1, several response variables 
had changed significantly after 12 months. Lean body 
mass and the average density of the lumbar vertebrae 
increased by 8.8 percent (P<0.0005) and 1.6 percent 
(P<0.04), respectively, and adipose-tissue mass de- 
creased by 14.4 percent (P<0.005). The sum of skin 
thicknesses at four sites increased 7.1 percent (P = 
0.07). The small average change in lumbar vertebral 
bone density (only 0.02 g per square centimeter) was 
statistically significant because of very little variability 
in individual results. The bone density of the radius 
and proximal femur and the ratio of the height of the 
alveolar ridge to total mandibular height did not 
change significantly. In group 2 none of these variables 
changed significantly. The change in the lean body 
mass was significantly greater in group 1 than in 
group 2 (P<0.018), but the differences in changes in 
skin thickness and adipose-tissue mass between 
groups did not reach statistical significance in this 
small series (P = 0.10 and 0.13, respectively). 

Table 3. Effect of the Administration of Human Growth Hormone on Plasma IGF-I Concentrations in Healthy Older Men.* 


Plasma IGF-I 



mo 1 

mo 3 

mo 6 

mo 7 mo 8 
units per liter 

mo 9 

mo 10 

mo 1 1 

mo 12 

Group 1 

240 ±86 



830 + 339t 680+180f 

720 + 350J 




Group 2 

240 ±69 



200+126 220+123 




300 ±201 

*Values arc r 

ncans ±SD. 

tP<0.05 for the eompariso! 

l between groups. 

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July 5, 1990 

Table 4. Effect of the Administration of Human Growth Hormone on Weight, Lean 
Body Mass, Adipose-Tissue Mass, Skin Thickness, and Bone Density in Healthy 

Older Men.* 



End of 



End of 



P Value! 


nce in Changes^ 

Weight (kg) 


83.3 + 11.1 


83.3 + 9.7 



+ 1.0 

-1.4 to +3.4) 

Lean body mass (kg) 


53.0 + 7.4 
54.2 + 7.1 

57.7 + 9.1 
55.2 + 7.3 


+ 3.7 

+ 0.7 to +6.6) 

Adiposc-tissuc mass (kg) 



20.6 + 5.6 



-5.7 to +0.8) 

Sum of skin thickness at 
four sites (mm) 






-0.1 to +1.7) 

Bone density (g/cm 2 ) 
Mid-shaft radius 



0.71 + 0.07 


+ 0.04 

-0.02 to +0.10) 

Distal radius 






-0.03 to +0.02) 

Average, lumbar 
vertebrae 1—4 



1.25 + 0.13 


+0.006 ( 

-0.04 to +0.05) 

Ward's triangle 







-0.08 to +0.05) 

Greater trochanter 



0.85 + 0.13 
0.81 + 0.13 


+ 0.007 ( 

-0.05 to +0.03) 

Femoral neck 







-0.08 to +0.03) 

Mandibular-hcight ratio 



0.46 + 0.11 
0.47 + 0.12 




-0.07 to +0.06) 

*Plus-minus values are means ±SD. 

|P values are for the change from base line, by matehed-pair t-test. 

iThe difference in changes (12-month value minus 6-month value) is the average change in group 1 minus the average 
change in group 2. Values in parentheses are 95 percent confidence intervals, calculated by independent-sample, unequal- 
variance t-tests. 


The 21 men studied were representative of the ap- 
proximately one third of all men 60 to 80 years old who 
have plasma IGF-I concentrations of less than 350 U 
per liter (as compared with a range of 500 to 1500 U per 
liter in healthy men 20 to 40 years old). 4 Our findings 
cannot be generalized to the approximately two thirds 
of all men over 60 who have plasma IGF-I concentra- 
tions of more than 350 U per liter or to women of a 
similar age. Furthermore, our entry criteria focused 
the study on an overtly healthy subgroup of older men. 

In the absence of obesity, 4 below-normal weight, 20 
or liver disease, 21 a plasma IGF-I concentration of less 
than 350 U per liter in older men generally signifies 
that they secrete very little growth hormone. 4 To verify 
this explanation for the low plasma IGF-I concentration 
in these men, it would be necessary to measure serum 
growth hormone levels at frequent intervals for 24 
hours or to determine the 24-hour urinary excretion of 
growth hormone. We did not do this, but Ho et al. found 
that the 24-hour integrated serum growth hormone lev- 
el was markedly lower in the men over 55 than in men 
18 to 33 years old. 22 An alternative explanation for a low 
plasma IGF-I concentration is decreased production of 
plasma IGF-I binding proteins. Most of the IGF-I plas- 
ma is bound to these proteins, but their concentrations 
vary little in healthy people who eat a normal diet. 

In the 12 men in group 1, initially 
low plasma IGF-I concentrations 
were raised to the normal range for 
young adult men by the dose of 
growth hormone administered, with 
no evidence of tachyphylaxis or hor- 
mone resistance. The dose, approxi- 
mately 0.03 mg per kilogram three 
times a week, was based on pub- 
lished estimates of the rate of 
growth hormone secretion in young 
men 23 and was comparable to or 
smaller than doses given previously 
to children with growth hormone 
deficiency 24 ' 25 and young adults. 10 " 13 
The plasma IGF-I responses to this 
dose in these older men were similar 
in magnitude to those in younger 
people. That "replacement" rather 
than pharmacologic doses were be- 
ing administered was confirmed by 
the plasma IGF-I measurements, 
which remained within the range for 
healthy young adults (500 to 1500 U 
per liter) throughout the treatment 
period (Table 3). We conclude that 
in aging men with low plasma IGF-I 
concentrations hepatic responsive- 
ness to human growth hormone is 
not impaired, and the decline in 
plasma IGF-I concentrations in such 
men results from growth hormone 
deficiency rather than growth hor- 
mone resistance. The increase in plasma IGF-I levels 
that occurs when growth hormone is administered to 
children with growth hormone deficiency reflects not 
only augmented hepatic production of IGF-I, but also 
increased production of one of the binding proteins 
that transport IGF-I. 26 The extent to which the pro- 
duction of IGF-I binding protein is increased by the 
administration of growth hormone has not yet been 
studied in adults. 

At the beginning of our study, adverse reactions to 
human growth hormone were thought to be unlikely 
because physiologic doses were being used. Further- 
more, similar or larger doses have not caused undes- 
ired reactions in children or young adults. 10 " 14 ' 23 Never- 
theless, it remained possible that this dose, when 
given for six months to older subjects, might cause 
some manifestation of hypersomatotropism, such as 
edema, hypertension, diabetes, or cardiomegaly. 2 '" 29 
Although none of these conditions developed, there 
were small increases in the mean systolic blood pres- 
sure and fasting plasma glucose concentration of the 
group of men who received growth hormone. 

The magnitude of the increases in lean body mass 
and the decreases in adipose-tissue mass (8.8 and -14.2 
percent above and below base line, respectively) in the 
aging men who received human growth hormone for 
six months was similar to the magnitude of these re- 

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Copyright© 1990 Massachusetts Medical Society. All rights reserved. 

Vol. 323 No. 1 


sponses in children 8,9 and young adults 10 " 13 treated 
with similar or lower doses for three to six months, a 
comparison that provides further evidence that tissue 
responsiveness to growth hormone and IGF-I is not al- 
tered in older men. Until now, the evidence for such a 
conclusion came only from short-term nitrogen-bal- 
ance experiments. 14,30 " 32 

Salomon et al. reported that the administration of 
human growth hormone in a dose of 0.49 unit per kilo- 
gram per week (0.19 mg per kilogram per week) for six 
months to adults 20 to 50 years old who had growth 
hormone deficiency lowered the serum cholesterol con- 
centration significantly. 13 Serum cholesterol concentra- 
tions did not change in our study, in which the dose of 
growth hormone was about half as large (0.9 mg per 
kilogram per week). The divergent results could reflect 
differences in the subjects' ages, the degree of growth 
hormone deficiency, the dose of hormone, or all three. 

In rodents, the increase in lean body mass in re- 
sponse to growth hormone is due to increases in the 
volume of skeletal muscle, skin, liver, kidney, and 
spleen. 1,7 In young human subjects, an enlargement of 
muscle and kidney induced by growth hormone has 
been documented 8 " 12 ; other organs have not yet been 
assessed. The reduction in adipose-tissue mass when 
children with growth hormone deficiency are treated 
with human growth hormone is associated with a re- 
distribution of adipose tissue from abdominal to pe- 
ripheral areas. 31 It is not known, however, whether the 
increase in lean body mass and the decrease in adi- 
pose-tissue mass are qualitatively as well as quantita- 
tively similar in old and young human subjects. 

Biosynthetic human growth hormone had no detect- 
able effect on the bone density of the radius or proxi- 
mal femur in the aging men, but it increased the den- 
sity of the lumbar vertebrae by about 1.6 percent. 
Although the decrease in bone density with advancing 
age in men may be due in part to diminished secretion 
of growth hormone, 1,33 longer periods of administration 
of human growth hormone will be required before a fi- 
nal conclusion can be drawn regarding its efficacy in 
reversing that decrease. A similar interpretation applies 
to the lack of increase in the mandibular-height ratio. 

The findings in this study are consistent with the hy- 
pothesis that the decrease in lean body mass, the in- 
crease in adipose-tissue mass, and the thinning of the 
skin that occur in older men are caused in part by re- 
duced activity of the growth hormone-IGF-I axis, and 
can be restored in part by the administration of human 
growth hormone. 1,2 The effects of six months of human 
growth hormone on lean body mass and adipose-tissue 
mass were equivalent in magnitude to the changes in- 
curred during 10 to 20 years of aging. 1,34,35 Among the 
questions that remain to be addressed are the follow- 
ing: What will be the benefits and what will be the na- 
ture and frequency of any adverse effects when larger 
numbers of elderly subjects and other doses of human 
growth hormone are studied? What organs are respon- 
sible for the increase in lean body mass, and do their 
functional capacities change as well? Only when such 

questions are answered can the possible benefits of hu- 
man growth hormone in the elderly be explored. Since 
atrophy of muscle and skin contributes to the frailty of 
older people, the potential benefits of growth hormone 
merit continuing attention and investigation. 

We are indebted to Dr. Ruth Hartmann, Milwaukee Veterans Af- 
fairs Medical Center, for assistance in the preparation of this report. 


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